Looking for the ideal medication for heart failure with reduced ejection fraction: a narrative review

The main goals of the pharmacological treatment of Heart failure with reduced ejection fraction (HFrEF) are the reduction of mortality and the prevention of hospitalizations. However, other outcomes such as improvements in cardiac remodeling and clinical status, functional capacity and quality of life, should be taken into account. Also, given the significant inter-individual and intra-individual variability of HF, and the fact that patients usually present with comorbidities, an appropriate treatment for HFrEF should exert a clinical benefit in most patient profiles irrespective of their characteristics or the presence of comorbidities, while providing organ protection beyond the cardiovascular system. The aim of this narrative review is to determine which are the proven effects of the guideline-directed treatments for HFrEF on five key clinical outcomes: cardiovascular mortality and hospitalization due to HF, sudden death, reverse cardiac remodeling, renal protection and evidence in hospitalized patients. Publications that fulfilled the pre-established selection criteria were selected and reviewed. Renin-angiotensin system (RAS) inhibitors, namely angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARBs) or angiotensin receptor-neprilysin inhibitors (ARNI), beta-blockers (BB), mineralocorticoid receptor antagonists (MRA), sodium-glucose co-transporter 2 inhibitors (SGLT2i) show a benefit in terms of mortality and hospitalization rates. ARNI, BB, and MRA have demonstrated a significant positive effect on the incidence of sudden death. ARB, ARNI, BB and SGLT2i have been associated with clear benefits in reverse cardiac remodeling. Additionally, there is consistent evidence of renal protection from ARB, ARNI, and SGLT2i in renal protection and of benefits for hospitalized patients from ARNI and SGLT2i. In conclusion, the combination of drugs that gather most beneficial effects in HFrEF, beyond cardiovascular mortality and hospitalization, would be ideally pursued.


Introduction
Hearth failure (HF) with reduced ejection fraction (HFrEF) is characterized by a left ventricular ejection fraction (LVEF) of ≤40% (1).HFrEF accounts for 66% of new-onset HF cases (2), and incidence rates are lower in women than in men (3).In a study of more than 2,300 ambulatory patients with HFrEF with an all-cause mortality rate of 33%, around 75% of patients died due to HF-related factors.This rate was lower in patients with LVEF over 40% (4).HF also contributes to the hospitalization burden: within 5 years after the diagnosis, 83% of patients with HF are hospitalized at least once, and 43% are hospitalized four or more times (5).Hospitalization, in turn, reduces survival rates vs. general population, and this effect is even greater in recurrently hospitalized patients (6).Additionally, hospitalization accounts for 76% of HF-associated costs (7).Also, the risk of sudden death (SD) among patients with HFrEF, although decreasing over time with the increasing use of evidence-based medications (8), still remains a major factor.In light of these data, two of the goals of the pharmacological treatment are the reduction of mortality and the prevention of recurrent hospitalizations (1,9).
However, other outcomes should be taken into account when choosing the most appropriate drug in patients with HFrEF.Current guidelines state that improvement in clinical status, functional capacity, and quality of life of patients are the third goal of pharmacotherapy (1).HF is a dynamic condition and patients exhibit inter-individual and intra-individual variability, and differences are observed throughout the course of the disease (10).Consequently, the most appropriate treatment should exert a clinical benefit in most patient profiles and be efficient irrespective of patient characteristics (sex, age, etiology, LVEF, or the presence of comorbidities, among others).Patients with HF have a high comorbidity burden (11,12), so the most appropriate treatment should provide organ protection beyond the cardiovascular system.Finally, adherence and appropriate dosing are crucial for achieving clinical benefit and protection and are directly related to survival and the reduction of HF-associated hospitalizations (13,14).
In this article we review the suitability of each pharmacotherapeutic option for the treatment of patients with HFrEF, considering the four pillars based on guideline-directed medications: RAS blockers (ACE-I, ARB) or ARNI, BB, MR and SGLT2i.

Methods
For this narrative review we searched in the PubMed database merging our therapeutic classes of interest and the described clinical outcomes.The terms used for the search were ACEi, ARB, ARNI, BB, MRA and SGLT2i, in combination with cardiovascular mortality and HF, hospitalization and HF, SD and HF, reverse cardiac remodelling and HF, renal protection and HF or hospitalized patients and HF.We have analyzed a total of 48 studies of which 32/48 (66.6%) were double-blind randomized clinical trials (24 placebo-controlled, 8 of them controlled with an active comparator), 2/48 (4.2%) was an open-label randomized clinical trial, 9/48 (18.8%) were post hoc analysis of randomized clinical trials, 3/48 (6.3%) were cohort studies and 2/48 (4.2%) were meta-analysis.

Results
Effects of pharmacological treatment for heart failure on cardiovascular mortality and hospitalization due to heart failure All approved therapeutic options for HFrEF exert a positive effect on cardiovascular mortality and hospitalization due to HF (Table 1).The CONSENSUS trial evaluated the effect of the ACEi enalapril compared to placebo on the prognosis of severe congestive HF.Conventional treatment for HF continued in both groups.After 6 months of treatment, a 40% reduction of total mortality was observed in the enalapril arm (P = 0.002).Mortality due to progression of HF also decreased by 50% in the enalapril arm (P < 0.001) (15).Regarding the effect of enalapril on hospitalization, the SOLVD trial showed that the addition of enalapril to conventional therapy produced a 26% reduction in the rate of events after 48 months, defined as either death or hospitalization of patients, compared to placebo (P < 0.0001) (16).
The PARADIGM-HF trial, a double-blind RCT, evaluated the effect of sacubitril/valsartan vs. enalapril added to recommended therapy on a composite endpoint of death from cardiovascular causes or hospitalization due to HF in 8,442 patients with HFrEF.Median follow-up was 27 months.Sacubitril/valsartan was superior to enalapril in reducing the risks of either cardiovascular death or HF-associated hospitalizations (P < 0.001), cardiovascular death (P < 0.001), and the risk of first hospitalization for HF (P < 0.001) (20).Another study examined the effect of sacubitril/valsartan on the risk of clinical progression compared to enalapril.Sacubitril/valsartan was associated with a 23% reduction in hospitalizations for worsening HF (P < 0.001).Sacubitril/valsartan also reduced the risk of other manifestations of disease progression, such as intensification of treatment, emergency room visits, cardiovascular-related hospitalizations, hospitalizations due to any cause, or need for intensive care.The 40% reduction in HF-associated hospitalization was significant within the first 30 days after randomization (21).A third study evaluated the time-averaged proportional change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration after 4 and 8 weeks of either sacubitril/valsartan or enalapril alone after hemodynamic stabilization in patients with HFrEF hospitalized due to acute decompensation.Sacubitril/valsartan therapy led to a greater reduction in the NT-proBNP concentration (P < 0.001) after 8 weeks of treatment ( 22).In the TRANSITION study, the reduction in NT-proBNP concentration was evaluated in patients with stabilized acute decompensated HFrEF who initiated sacubitril/valsartan either before or after discharge.Starting treatment in the hospital produced a greater reduction of NT-proBNP at discharge (23).
BB have also shown a clear benefit in terms of cardiovascular mortality and hospitalizations due to HF.In the CIBIS-II study, after 15 months of treatment, a 26% reduction in the risk of cardiovascular mortality (P = 0.0049) and a 31% reduction in hospital admission for worsening HF (P < 0.0001) were reported in the bisoprolol arm compared to placebo.All-cause mortality was also significantly lower in patients treated with bisoprolol (25).Another study comparing the effect of carvedilol to placebo showed a reduction in the mortality risk of 65% (P < 0.001) in the carvedilol group after 12 months.A 27% reduction in the risk of hospitalization due to cardiovascular causes (P = 0.036) and a 38% reduction in the risk of either hospitalization or death (P < 0.001) were also reported (24).A third double-blind randomized controlled study (MERIT-HF) enrolling almost 4,000 patients with chronic HFrEF showed that all-cause mortality was lower with metoprolol than with placebo (RR, 0.66, P = 0.00009) after 12 months of treatment; the risk of death from worsening HF was also lower with metoprolol (RR, 0.51, P = 0.0023) (26).
The risk of mortality and hospitalization has also been assessed in patients treated with MRAs.In an initial study of 1,663 patients (RALES) with severe HFrEF treated with ACEi, loop diuretics and digoxin showed a 30% reduction in death from any cause after the addition of spironolactone compared to placebo (P < 0.001) after 24 months.Death from cardiac causes was reduced by 21% in patients treated with spironolactone (P < 0.001), hospitalization from cardiac causes was reduced by 30% (P < 0.001), and the combination of both endpoints by 32% (P < 0.001) (27).In a second study with 2,737 patients with HFrEF treated with either eplerenone or placebo added to recommended therapy, the primary outcome was a composite of death from cardiovascular causes or hospitalization for HF: a reduction of 37% was observed in the intervention arm (HR, 0.63; 95% CI, 0.54-0.74;P < 0.001).The risk of death from any cause and the risk of hospitalization for HF were also significantly reduced (28).
SGLT2i have demonstrated a protective effect in patients with established HFrEF.The DAPA-HF study assessed the effect of dapagliflozin or placebo added to recommended therapy on the worsening of HF and cardiovascular death.A composite endpoint of worsening HF (including hospitalization or urgent visits requiring intravenous treatment) or cardiovascular death was significantly reduced in the dapagliflozin group (P < 0.001), as were each of those endpoints alone.The reduction in the primary event with dapagliflozin was rapidly statistically significant (28 days post-randomization), meaning that the benefit of the drug manifests promptly (29).Another study (EMPEROR-reduced trial) evaluated the efficacy of empagliflozin in patients with the same profile.Empagliflozin reduced by 24% the combined risk of death, hospitalization for HF or an emergent/urgent visit requiring intravenous treatment for HF (P < 0.0001).This benefit also reached early statistical significance (12 days after randomization) (30).

Effects of pharmacological treatment for heart failure on sudden death
Results obtained on the effect of the different therapeutic options on SD are summarized in Table 2.There were no differences in the incidence of SD between enalapril and placebo groups in either the CONSENSUS trial or SOLVD (15,16).
The clinical evidence on ARNI shows a clear benefit in the reduction of the incidence of SD in patients with HFrEF.Mode of death was adjudicated by a blinded clinical endpoints committee and, at the end of a 42-month follow-up period (mean follow-up was 27 months), the risk of SD was reduced by 20% (P = 0.008) while the risk of death from worsening HF was also reduced by 21% (P = 0.034) (33).
Several studies have addressed the incidence of SD in patients with HFrEF treated with BB (36).The CIBIS-II study reported a 44% reduction in the risk of SD (P = 0.0011) with bisoprolol compared to placebo (25).In the MERIT-HF study, there was a 41% reduction in SD (P = 0.0002) in the metoprolol group compared to the placebo group (26).Results obtained with carvedilol were similar and a 55% reduction was reported (24).
An overall benefit for MRA has been observed in the reduction of SD.In the RALES study, a 29% reduction in the relative risk of SD (P = 0.02) was described in the arm treated with spironolactone compared to the arm treated with placebo (27).In contrast, in the EMPHASIS-HF study, the reduction in the relative risk of SD of 24% with eplerenone vs. placebo was not statistically significant (P = 0.12) (28).A subsequent metaanalysis evaluated the relative risk reduction of SD with any MRA compared to control arms.Eight randomized controled trials that included almost 12,000 patients met the inclusion criteria; five examined the role of spironolactone, two eplerenone, and one canrenone.MRAs were  associated with a 23% reduction in sudden cardiac death compared to controls (P = 0.001).Similar reductions were observed in cardiovascular and total mortality (34).The effect of SGLT2i on SD was examined in a post hoc analysis of the DAPA-HF study.Dapagliflozin significantly reduced a composite endpoint of serious ventricular arrhythmia, resuscitated cardiac arrest, and SD compared to placebo, but the effect on SD alone was not significant (35).
Effects of pharmacological treatment for heart failure on reverse cardiac remodeling Some differences have been shown in the effect of the different therapeutic options on reverse cardiac remodeling (Table 3).A substudy from the SOLVD study was carried out to elucidate whether enalapril inhibited remodeling in the patients enrolled.A pool of 301 patients from 5 centers were examined using Doppler echocardiography before randomization and after 4 and 12 months of therapy with either enalapril or placebo.EF remained unchanged in both arms after 12 months (37).The CARMEN study evaluated the suitability of the combination of ACEi and BB for the treatment of chronic HFrEF, as well as the recommendation to initiate treatment with ACEi and only add BB in symptomatic patients.Regarding reverse cardiac remodeling, in patients treated with enalapril, changes in LVEF were not significant at 6 and 12 months and were statistically greater at 18 months (38).
Clinical evidence with ARNI has demonstrated also a clear benefit in terms of reverse cardiac remodeling.The PROVE-HF study enrolled 794 patients with HFrEF who were switched from ACEi/ARB to ARNI therapy.At 6 months, left ventricle and left atrial volume indexes, E/e' ratio, LV mass index and LVEF were significantly improved compared to baseline.After 12 months, sacubitril/valsartan produced a mean LVEF increase of 9.4%.Moreover, 25% of patients experienced a LVEF increase of 13.4% or more.Patients with new-onset HF or who were ACEi/ARB naive at baseline showed mean improvements in LVEF of 12.8% (44).
In the aforementioned CARMEN study, patients receiving carvedilol monotherapy showed a significant increase in LVEF at 6, 12 and 18 months (38).The REVERT study elucidated the effect of therapy with the BB metaprolol on left ventricular remodeling in asymptomatic patients with left ventricular systolic dysfunction.A total of 149 patients were randomized to three treatment groups (200 mg, 50 mg, and placebo).LVEF increased significantly in patients treated with metoprolol after 6 months compared to placebo.After 12 months, LVEF remained unchanged in the placebo group, but increased significantly by 3.9% in patients receiving 50 mg metoprolol and by 6.2% in patients receiving 200 mg metoprolol.Changes were similar at 6 months (45).
A randomized control trial examined the effect of spironolactone on LV function and the functional capacity of patients with mild to moderate HF.LVEF increased from 35.2% to 39.1% ± 3.5% after 6 months of spironolactone treatment, while the placebo arm showed no significant differences (P = 0.003) (46).A second study evaluated the effect of eplerenone added to contemporary background therapy on ventricular remodeling in patients with HFrEF.After 36 weeks of treatment, no effects were observed in left heart remodeling parameters with eplerenone compared to placebo (47).Thus, the clinical evidence obtained with MRA in reverse cardiac remodeling is limited and inconsistent.
In the case of SGLT2i, the sample size of the studies addressing reverse cardiac remodeling to date is limited.The REFORM study only included 56 patients assigned to either dapagliflozin or placebo and no statistically significant effect was observed on LVEF changes at 12 months (48).Another study evaluating the role of empagliflozin on LV function and volumes in 84 nondiabetic HFrEF patients showed a statistically significant improvement in LV volumes, LV mass and LVEF at 6 months of treatment (49).Recently, the DAPA-MODA, a single-arm study including 162 patients (48% LVEF ≤40%, 52% LVEF >40%) showed a favorable and significant impact of dapagliflozin in both atrial and ventricular remodeling parameters including an increase of 5% in LVEF (p = 0.040), assessed by echocardiography and interpreted in a blinded manner (50).

Effects of pharmacological treatment for heart failure on renal protection
HF is associated with a greater decline in renal function over time.However, not all available HF treatments exert a positive effect on renal function (Table 4).In the SOLVD study, more patients receiving enalapril showed a serum creatinine increase of at least 2 mg/dl or a potassium increase of at least 5.5 mmol/L than in the placebo arm (P < 0.01) (16).In the CONSENSUS trial, however, the increase in serum creatinine levels did not lead to significant differences in treatment discontinuation between the enalapril and placebo arms (15).Clinical evidence suggests a beneficial clinical effect even in patients with HFrEF who suffer a decline in renal function after initiating treatment with ACEi (57).However, there is no clinical evidence to show that ACEi reduces the risk of lower eGFR.Similar data are available for ARBs (58).In addition, baseline chronic kidney disease (CKD) should not preclude ACEi/ARB use, as their efficacy persists in CKD, supported by trials like CONSENSUS, SOLVD, ValHeFt, and CHARM (59).However, specific studies on RAAS inhibitors in advanced CKD (GFR <15 ml/min/ 1.73 m 2 ) are limited, and safety should be confirmed in long-term observational studies.KDIGO guidelines recommend ACEi and ARBs in CKD stage 5, with moderate evidence for use in dialysis and weak evidence for non-dialysis patients (60).
In the PARADIGM-HF trial, adverse events due to serum creatinine levels ≥ 2.5 mg/dl and serum potassium levels > 6.0 mmol/L were less frequent with sacubitril/valsartan than with enalapril (P < 0.05 for both comparisons) (20).A comprehensive analysis of the PARADIGM-HF trial illustrated a clear 37% reduction in renal function decline among patients treated with sacubitril/valsartan compared to patients treated with enalapril.Additionally, sacubitril/valsartan showed a consistent clinical benefit for cardiovascular death and hospitalization in the HF composite outcome, irrespective of the presence or absence of chronic kidney disease (52).Another study assessed differences in the effect of sacubitril/valsartan on renal function in patients with type 2 diabetes mellitus (T2DM).Patients treated with sacubitril/valsartan showed a slower decline in eGFR than those treated with enalapril.The difference between the sacubitril/ valsartan and the enalapril arms observed in patients with T2DM was twice as high as that observed in patients without T2DM (53).A subsequent secondary analysis of the PARADIGM-HF trial described how sacubitril/valsartan reduced the risk of severe hyperkalemia compared to enalapril in patients treated with MRA at baseline (54).
Clinical evidence on the effect of BB on renal function is limited.Their use does not cause renal function to worsen over time, as is the case with ACEi.Several studies have reported that patients in the lowest GFR strata show a greater relative risk reduction with BB (57, 61, 62).No adverse events related to the worsening of renal function were reported in the randomized clinical trials addressing the effect of carvedilol on mortality and morbidity in patients with HFrEF (24, 55).
MRA does not seem to exert a protective effect on renal function.In fact, spironolactone was associated with significant but not clinically relevant increases in creatinine and potassium (27).In EMPHASIS study, eplerenone was associated with a significant but not clinically relevant serum potassium increase at one month and at the cutoff date, and with a non-significant increase in serum creatinine (28).In the EPHESUS study, eplerenone produced a decline in eGFR compared with placebo (P < 0.0001) that appeared within the first month and lasted throughout the 24-month follow-up (63).Thus, the initiation of treatment with MRA produces an acute decline in eGFR that is maintained throughout administration (57).
Two studies have corroborated the renal protective effect of SGLT2i.In the DAPA-HF trial, the percentage of patients with worsening renal function was similar in the dapagliflozin and placebo arms (29).In a post hoc analysis of the same study, a composite renal outcome (≥50% sustained decline eGFR or endstage renal disease or renal death) was not reduced by dapagliflozin, although the rate of decline in eGFR between day 14 and 720 was less with dapagliflozin than with placebo (56).In the EMPEROR-REDUCED trial, a composite renal outcome was assessed in patients treated with either empagliflozin or placebo, and a statistically significant difference emerged in favor of  empagliflozin (30).Both studies demonstrated a reduction in the risk of worsening renal function.

Effects of pharmacological treatment for heart failure on hospitalized patients
The effect of the different therapeutic options on hospitalized patients is summarized in Table 5.To date, no robust data are available from randomized controlled trials on the initiation of ACEi in hospitalized patients (71).The CONSENSUS study, for instance, only included 253 hospitalized patients from a total of 1,987 recruited patients ( 15).
An analysis of the GWTG-HF registry revealed that hospitalized patients who continued ACEi/ARB therapy experienced significantly lower mortality rates at 30 days, 90 days, and 1 year, as well as reduced 30-day readmission rates, compared to those who discontinued ACEi/ARB therapy (64).
ARNI have shown clinical benefit in hospitalized patients.In a subanalysis of the PIONEER-HF study, a 46% reduction was recorded in the combined risk of death, readmission for HF, need for LV assistance or inclusion in a heart transplantation waiting list (65).In another study (PIONEER-HF), patients with de novo HF had lower risk of either cardiovascular death or rehospitalization for HF than patients with previous history of HF.Likewise, patients not treated with ACEi or angiotensin receptor blockers at admission also showed a significantly lower incidence of the same composite endpoint (66).
The IMPACT-HF study, a prospective trial in 363 patients, showed a non-significant trend towards a benefit in terms of a lower composite of death or rehospitalization for the predischarge initiation of carvedilol in stabilized patients compared to initiation of any BB more than two weeks after discharge (67).A meta-analysis that included five observational studies and one randomized clinical trial showed that the discontinuation of BB in patients admitted to hospital was associated with increased in-hospital and short-term mortality (68).
No randomized clinical trials have addressed the role of MRA in hospitalized patients and available evidence is currently limited to a single-center observational study of 685 patients discharged after admission for acute HF.In this study, starting MRA in the hospital was associated with significantly lower mortality than late initiation (69).In contrast, the EMPULSE trial (empagliflozin) showed a clear clinical benefit in the composite endpoint (death from any cause, number of HF events and time to first HF event, or a 5-point or greater change from baseline in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score at 90 days) (70).

Discussion
This review highlights that the current guideline-directed medications (ACEi/ARB/ARNi + BB + MRA + SGLT2i) have a positive effect on the main components of disease progression in HFrEF patients.However, the extent of protection varies among these drugs (Graphical Abstract).All medications prevent cardiovascular mortality and HF hospitalization (15-30), but ACEi lack clear evidence for SD, renal protection, or benefits in hospitalized patients, possible due to older studies (15, 16,71).ARNI (sacubitril-valsartan) extends benefits beyond ACEi/ARB, showing improvements in all disease progression components, and is increasingly recommended over ACEi (20-23, 33, 44, 52-54, 65, 66).
The benefit of BB is clear for decades, with numerous trials supporting the effect on cardiac protection and the reduction of Frontiers in Cardiovascular Medicine 13 frontiersin.orgrelated complications, with a neutral effect in renal function (24,25,55,57,61,62).MRAs are limited by the risk of hyperkalemia in kidney disease (27).Finally, SGTL2i, the last pillar incorporated to HFrEF, significantly reduce the risk of HF decompensation and improve renal protection, with less evidence on cardiac remodeling and SD (29,30,35,(48)(49)(50)56).
In conclusion, all currently recommended medications for HFrEF have a positive effect on mortality and hospitalization rates.Considering the relevance of preventing SD as mode of death, ARNI, BB, and MRA are particularly effective.In addition, organ protection should be considered.In this regard, ARNI, BB, and SGLT2i improve LVEF and reverse parameters of cardiac remodeling, with ARNI and SGLT2i also offering renal protection.Likewise, it is important to consider effective and safe medications within the early phase of HF hospitalizations, and ARNI and SGLT2i are the main options in this acute setting (Figure 1).Therefore, although we have not a single ideal medication, the optimal therapy combines ARNI, BB, MRA and SGLT2i to maximize benefits across all disease progression aspects.

TABLE 1
Effect of pharmacological treatment on cardiovascular mortality and hospitalization due to heart failure.

TABLE 2
Effect of pharmacological treatment on sudden death.

TABLE 3
Effect of pharmacological treatment on reverse cardiac remodeling.

TABLE 4
Effect of pharmacological treatment on renal protection.

TABLE 5
Effect of pharmacological treatment in hospitalized patients.